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Griffes was born in Elmira, New York. He had early piano lessons with his sister Katherine and later studied piano with Mary Selena Broughton, who taught at Elmira College. Mary had a profound impact on his personal and musical development.[2] After early studies on piano and organ in his home town, on recommendation of Broughton, he went to Berlin to study with pianist Ernst Jedliczka and Gottfried Galston at the Stern Conservatory.[3] Although recognised as a performer, Griffes grew more interested in composition. Despite being advised against it by Broughton, he left the conversatory and was briefly taught by composer Engelbert Humperdinck.[2][3]. During his time in Berlin he composed several German songs and the Symphonische Phantasie for orchestra.[2]

On returning to the U.S. in 1907, he became director of music studies at the Hackley School for boys in Tarrytown, New York, a post which he held until his early death thirteen years later.[4] His post has been described as "grim and unrewarding", though it gave him financial stability. He continued to compose at Hackley in his free time and promoted his music during the summer.[2]

Griffes' initial works are influenced by German Romanticism, but after he relinquished the German style,[2] his later works make him the most famous American representative of musical Impressionism. He was fascinated by the exotic, mysterious sound of the French Impressionists, and was compositionally much influenced by them while he was in Europe.[2] He also studied the work of contemporary Russian composers (for example Scriabin), whose influence is also apparent in his work, for example in his use of synthetic scales.

His most famous works are the White Peacock, for piano (1915, orchestrated in 1919); his Piano Sonata (1917–18, revised 1919); a tone poem, The Pleasure Dome of Kubla Khan, after the fragment by Coleridge (1912, revised in 1916), and Poem for Flute and Orchestra (1918). He also wrote numerous programmatic pieces for piano, chamber ensembles, and for voice. The amount and quality of his music is impressive considering his short life and his full-time teaching job, and much of his music is still performed. His unpublished Sho-jo (1917), a one-act pantomimic drama based on Japanese themes, is one of the earliest works by an American composer to show direct inspiration from the music of Japan.

Charles Tomlinson Griffes was drawn into the gay world by the baths not just because he had sex there, but because he met men there who helped him find apartments and otherwise make his way through the city, who appreciated his music, who gave him new insights into his character, and who became his good friends. The gay world became a central part of his everyday world, even though he kept it hidden from his nongay associates.

— George Chauncey, Gay New York 1995

During his time as a student in Berlin he was devoted to his "special friend" Emil Joèl (aka "Konrad Wölcke"). In later life, he had a long term relationship with John Meyer (biographer Edward Maisel used the pseudonym Dan C. Martin), a married New York policeman.[6]